One promise of gene therapy is the ability to correct genetic defects responsible for disease by the addition to an individual of functional genetic material as well as the ability to deliver therapeutic proteins using genetic material that encodes such proteins. There is a great deal of activity in the development of protocols for treating diseases and disorders by administering a nucleic acid which codes for a polypeptide that is either missing or defective in an individual. Another promise of gene therapy is as an alternative and improved means to deliver therapeutically important proteins to individuals in need of such proteins. The discovery of proteins with therapeutically important functions has led to new treatments for many diseases and disorders and the application of gene therapy to deliver such proteins is also the subject of much interest.
Among the strategies for delivering genetic material, the use of immunogenic vectors, most commonly viral vectors, capable of infecting the individual's cells is the one of the most widely employed methodologies. Essentially, genetic material that encodes desired proteins, whether they be functional forms of defective genes responsible for disease or coding sequences for therapeutically useful proteins, is incorporated into the genome of a vector which has the ability to infect cells of the individual or otherwise deliver the genetic material to cells of the individual.
Adenovirus, adenovirus associated virus (AAV), vaccinia virus, and simian virus 4 (SV40) are just a few of the many viruses used to make viral vectors for gene therapy. In some cases, the viral vectors are selected for their ability to infect specific tissue to which delivery of the genetic material is desired. In some cases, the viral vectors are selected because they are attenuated and cause serious limited infections to the individual without significant pathology.
One of the major problems associated with gene therapy protocols that employ immunogenic vectors is that an immune response against the vector is induced in the individual who is administered the vector. The immune response targets the vector including cells which are infected by the vector. The destruction of cells which are infected by the vector reduces the efficacy of the treatment. Further, immune responses induced against the vectors limit the effectiveness of subsequent doses of the same gene therapeutic composition or other gene therapeutic compositions which use the same vector because the immune system of the individual will recognize the vector from the subsequent doses of the same gene therapeutic composition or other gene therapeutic compositions which use the same vector and mount an immune response similar to the manner in which a vaccine protects the individual from subsequent exposure to a pathogen.
There are two branches to the immune system. The humoral branch of the immune system involves antibodies which are secreted by B lymphoid cells and recognize specific antigens. Binding of antibodies to specific antigens inactivates the antigen. Antibodies may also bind to the antigen and activate other immune cells which destroy the bound antigen.
The cellular branch of the immune system involves specific cell types which recognize and destroy cells which display “foreign” antigens. Cytotoxic T cells (also referred to as cytotoxic T lymphocytes or CTLs) are an example of cells in the cellular branch of the immune system. CTLs recognize fragments of peptides which are displayed on the plasma membrane surface bound to major histocompatibility complex molecules (MHCs). Cells that display a peptide which is “foreign” elicit a cellular immune response. Cytotoxic T cells then destroy the cell displaying foreign peptide fragments.
When a patient undergoes an organ or cell transplant or a tissue graft, the patient's immune system will recognize the donor organ, cells or tissue as “foreign” and mount an immune response against the donor organ, cells or tissue. Immunosuppressive drugs are used to down modulate the patient's immune response and prevent rejection.
In autoimmune disease, the immune system attacks “self” antigen. Some autoimmune diseases are T cell mediated. Examples of T cell mediated autoimnmune diseases include Rheumatoid arthritis (RA), multiple sclerosis (MS), Sjogren's syndrome, sarcoidosis, insulin dependent diabetes mellitus (IDDM), autoimmune thyroiditis, reactive arthritis, ankylosing spondylitis, scleroderma, polymyositis, dermatomyositis, psoriasis, vasculitis, Wegener's granulomatosis, Crohn's disease and ulcerative colitis. Other autoimmune diseases are B cell mediated. Examples of B cell mediated autoimmune diseases are Lupus (SLE), Grave's disease, myasthenia gravis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, asthma, cryoglobulinemia, primary biliary sclerosis and pernicious anemia. In both types, an immune response is directed at the body's own antigens. Autoimmune diseases may be treated by suppressing immune responses.
There remains a need for improved gene therapy vectors, compositions and methods which can be used to increase safety and efficacy. There remains a need for improved gene therapy vectors, compositions and methods which can reduce or elimnate the immune response against the viral vector which limits the ability to expose the individual to subsequent doses of the therapeutic or other therapeutics or vaccines employing the same vector. There is a further need for methods for suppressing immune responses associated with cell organ, cell and tissue transplants. There is a need for methods for delivering polypeptides to individuals while inhibiting the cellular immune response against the vector which encodes the desired polypeptide. There is a further need for methods for modulating immune responses associated with inflammatory and autoimmune diseases and disorders.